Dementia and stroke are increasing in prevalence. These neurological diseases are major causes of disability and institutionalization and place a crushing burden on individuals, caretakers and the government's healthcare budget. There is an unmet need for the discovery of novel markers that may be used for early detection, prevention, and point toward potential development of novel targets for therapeutics. Some of the strongest known risk factors for dementia and stroke are related to apolipoproteins, a broad class of proteins that transport a variety of compounds in aqueous solutions like the cerebrospinal fluid (CSF) and plasma. The apoE4 variant is the single strongest known risk factor for late onset Alzheimer's disease (AD), and recently apoJ was also identified in genome-wide association studies of AD. Other apolipoproteins, such as apoAI and apoCIII are also found in CSF, even though they aren't expressed there. Apolipoproteins determine the function and metabolism of lipoproteins (HDL and LDL) by mediating their interaction with receptors and enzymes. Thus far, the role of apolipoproteins in neurological disease has only been studied in a crude manner, and it has not yet been considered that apoE is found on both HDL and LDL; two lipoproteins with opposing associations with dementia and stroke. Further, it has not been examined whether the inverse association of HDL with stroke and dementia is attributable to its apoE content. The overall objective of this proposal is to investigate plasma apolipoprotein-defined HDL subspecies as novel risk markers for neurological disease. Our central hypothesis is that apolipoproteins of demonstrated importance to brain cholesterol and beta-amyloid (Ab) metabolism (apoJ, apoE and apoCIII) may identify subspecies of HDL that are more closely involved in the pathogenesis. In our laboratory we have developed a novel ELISA assay that can assess HDL subspecies according to apolipoprotein content. We have found that in contrast to the protective associations of total HDL and HDL without apoCIII, HDL with apoCIII lacks a beneficial association with diabetes and cardiovascular disease risk. We wish to leverage our proven laboratory technology to investigate HDL subspecies, defined on the basis of apoE, apoJ and apoCIII, in association with risk of dementia, stroke, cognitive decline, Ab deposition, and brain atrophy. In this project we will combine two research fields (lipoprotein biochemistry and neurology) in an innovative way to discover novel HDL subspecies that may contain more value for risk prediction than the traditionally used clinical measures of HDL-cholesterol. Our rationale for the proposed research is that apolipoprotein-defined HDL subspecies likely capture the functional correlates of HDL rather than just its average cholesterol concentration. We expect that the investigations of these minimally invasive plasma measures may lead to improved risk stratification and prevention.